Kielin/Chordin-Like Protein—A Novel Pathway to Prevent Renal Fibrosis?
Authors: J Lin, SR Patel, X Cheng, EA Cho, I Levitan, M Ullenbruch, SH Phan, JM Park, GR Dressler
Journal: Journal of the American Society of Nephrology (2005)

Since the classical observations of Schainuck et al. (1), Risdon et al. (2), and Bohle et al. (3), it has been known that interstitial fibrosis in the kidney is more predictive of the risk of progression than the frequency and severity of glomerular lesions. An important, although possibly not the only, mechanism leading to interstitial fibrosis is epithelial to mesenchymal cell transition (4–6)—a concept which had originally been received with a dose of skepticism because at the time it was widely believed that tubular epithelial cells are terminally differentiated. The evidence that has accumulated by now, however, leaves little doubt that this type of transition does indeed occur. The spectacular versatility of stem cells in adopting or changing differentiation pathways helped remove intellectual barriers to accept the concept of transdifferentiation. Epithelial to mesenchymal cell transition is a final common pathway of progression in response to a broad spectrum of insults such as ischemia, hypoxia, inflammation, etc. It implies that the tubular cells lose the epithelial phenotype and acquire fibroblast-specific characteristics such as fibroblast specific protein 1 (7), matrix metalloproteinases 2 and 9, interstitial type collagen, and others (6). As all important biologic processes, epithelial to mesenchymal transition is tightly regulated by numerous positive and negative regulators. Such multiplicity indicates that nature adheres to the philosophy of “not putting all of one’s eggs into one basket.” In the control of signaling relevant for renal fibrosis, mainly two members of the TGF-β superfamily are involved (8), interacting with receptors of different receptor superfamilies and using different intracellular signaling pathways. These comprise the positive regulator TGF-β and the negative regulator bone morphogenetic protein 7 (BMP7): TGF-β promotes and BMP7 prevents renal fibrosis and scarring. Specifically, the TGF-β–driven profibrotic effect is directly antagonized by BMP7 (9). Such a reciprocal relationship suggests that a delicate balance must be maintained. What do we know about BMP7 and the kidney? BMP7 is important in the embryonic development for the establishment of the dorsal/ventral pattern in invertebrates and vertebrates. In the kidney, it is necessary for branching and differentiation of tubules. In the adult organism, high doses of BMP7 attenuate, abrogate, or even reverse renal fibrosis in different models of renal damage (5,9–11). It is of interest to the clinical nephrologist that for this reason clinical studies on the efficacy of BMP7 in renal disease are currently underway. Parenthetically, BMP7 also ameliorates certain aspects of renal bone disease (12). A further level of complexity in the regulation of epithelial to mesenchymal transition has recently been identified, i.e., the trap proteins (8). These are proteins that trap the ligands in the extracellular milieu. Activation of the BMP7 receptor causes phosphorylation of the intracellular signaling substances Smad1, Smad5, and Smad8, thus interfering with the nuclear programs coding for proteins necessary for epithelial to mesenchymal transition. The trap proteins that interact with the ligands may either inhibit or amplify the effect on their signaling pathways. For BMP, an entire flock of negative, i.e., inhibitory, trap proteins is known, including noggin, chordin, short gastrulation (Sog), twisted gastrulation (Tsg), gremlin, follistatin, and others (13,14). They bind BMP and prevent contact with their receptors (15). It is here that the kielin/chordin-like protein (Kcp) described by Lin et al. (16) enters the picture. In contrast to the aforementioned proteins, Kcp doesn’t inhibit the action of BMP7, but is actually the first protein to amplify it. It is a secreted protein with 18 cysteine-rich signaling domains and is most homologous to Xenopous kielin (17). Kcp is thought to act as a paracrine promoter of BMP7 actions by elevating the intracellular concentration of the signaling molecule Smad1. It binds to BMP7 and enhances binding to the type I receptor of BMP7. What experiments did Lin et al. do to provide evidence for beneficial renal effects of the Kcp? Kcp knockout mice were fertile and viable. This finding is remarkable in view of the fact that BMP7, the action of which is amplified by Kcp, has an important role in tubulogenesis, and suggests that there is some redundancy of control mechanisms. The renal effects of Kcp became evident, however, when the Kcp knockout mice were exposed to two types of renal injury. In the model of unilateral ureteral obstruction, renal interstitial fibrosis was seen earlier and was more intense in the kidneys of Kcp knockout than in wild-type mice. Kcp expression, as well as levels of the BMP7-dependent signaling molecule Smad1, were upregulated in the obstructed kidney of wild-type mice, but were not demonstrable in the obstructed kidneys of knockout mice. With some time delay, expansion of the interstitial area as well as accumulation of collagen I were seen as well. So interfering with the action of BMP7 by removing the BMP7-activating molecule Kcp increased the severity of renal interstitial fibrosis. In addition, in the folic acid model of acute tubular necrosis, higher mortality and more severe renal scarring were seen in Kcp knockout mice, illustrating that the observation can be generalized to include different kinds of renal damage. Why are these findings of interest to the nephrologist? Despite the enormous progress achieved by blockade of the renin–angiotensin system and by other interventions to interfere with the progression of renal disease, these measures are not uniformly effective and there is still a desperate need for additional modalities of intervention. One such strategy may in the future be BMP7. It will then be important to identify factors that increase or decrease the efficacy of BMP7. For instance, it is conceivable that polymorphisms or conditions which increase or decrease the availability of Kcp determine the effectiveness of BMP7. We should also know which factors, e.g., renal disease or reduced renal function, modulate the availability of Kcp. In this context it is of interest that Lin et al. found increased Smad1 levels in the kidney contralateral to the obstructed one—possibly as a result of increased “workload.” Time will quickly tell whether the authors struck a gold mine or only chaff. My bet would be the former.